Delivery of drugs to mucosal surfaces

ABSTRACT

Liquid pharmaceutical compositions for administration to a mucosal surface, comprising a therapeutic agent and a pectin with a low degree of esterification are described. Such compositions gel, or can be adapted to gel, at the site of application in the absence of an extraneous source of divalent metal ions.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent application No.09/402,976, filed Jan. 20, 2000, which was a §371 filing ofInternational Application No. PCT/GB98/01147, filed Apr. 20, 1998,published in the English language on Oct. 29, 1998, under InternationalPublication No. WO 98/47535, the contents of each of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] This invention relates to an improved system for the delivery ofdrugs to mucosal surfaces such as the nose, the eye, the vagina, therectum and the back of the throat.

[0003] Administration of therapeutic agents to mucosa is well known inthe art.

[0004] A variety of drugs may be administered to the nose, includingthose intended for the local treatment of nasal diseases, nasalvaccines, and those intended for systemic circulation. Because the nosehas a reasonable surface area and a good blood supply, certainlipophilic drugs, such as nicotine and propranolol, can be absorbedrapidly into the blood, resulting in a bioavailability which is similarto that seen with intravenous injection. More polar drugs are less wellabsorbed, though absorption may be improved by the use of enhancingagents such as surfactants, powders such as microcrystalline cellulose,gelling microspheres (e.g., starch), and the bioadhesive polymer,chitosan. Examples of these systems are well known in the art and havebeen reviewed by Illum and Fisher in “Inhalation Delivery of TherapeuticPeptides and Proteins”, Adjei and Gupta (eds.) Marcel Dekker Inc., NewYork (1997) 135-184.

[0005] In a similar fashion, it is useful to deliver therapeutic agents,such as drugs and vaccines, to the vaginal cavity for a systemic effector for the local treatment of diseases (particularly infectious diseasessuch as candidiasis and bacterial vaginitis) as well as for prophylaxisof diseases (e.g., HIV). Locally acting formulations may also be used todeliver contraceptive and spermicidal agents.

[0006] Drugs may also be administered to mucosa in the eye and therectum in order to achieve local effects or for systemic activity.

[0007] Considerable advantages in terms of improved efficacy areexpected to be gained if a nasally administered formulation were capableof retaining a drug, a vaccine, or DNA intended for local effect, in thenose for relatively long time periods. Previous workers have used avariety of strategies for this purpose.

[0008] For example, Illum and others found that biodegradablemicrospheres based on materials such as starch could delay clearance toa period of hours as compared to a normal half life of clearance ofabout 10 to 15 minutes (Illum, et al., Int. J. Pharm., 39 (1986)189-199). Surprisingly, such systems were also found to give an improvedabsorption by affecting the integrity of the tight junctions of theepithelial cells in the nasal cavity and are expected therefore to bebest suited to drugs acting systemically.

[0009] Similarly, Illum and others have shown that the bioadhesivematerial chitosan can modify mucociliary clearance with an increase indrug absorption (Illum, et al., Pharm Res., 11 (1994) 1186-1189).

[0010] It would be most beneficial, due to ease of use and ofadministration, to have available a simple solution spray system thatwas suitable for the administration of drugs to the nose and, betterstill, for the drugs administered via such a system to have a longretention in the nasal cavity. The skilled person may envisage variousstrategies to this end, including the use of pharmacological agents thatdecrease mucociliary clearance by a direct effect on the action ofcilia, such as cocaine, as well as formulation methods such asenvironmentally-responsive gels.

[0011] Liquids that gel in response to a change in environment are knownto those skilled in the art. The environmental change can betemperature, pH or ionic strength or a combination of these factors.Examples of all of these systems can be found in the prior artliterature (see, for example, the smart hydrogel from Gelmed asdescribed by Potts et al in Proceed. Intern. Symp. Control Rel., 24, 335(1997)). However, the majority of these have been found to be unsuitablefor nasal use in man because of factors such as irritation, discomfort(e.g., administration of cold solutions), mucosal damage, an unwantedenhancement of drug absorption into the systemic circulation, and manyare unavailable due to lack of regulatory approval.

[0012] In summary, it would present considerable advantages to provide asingle component nasal delivery system, which was in the form of aliquid for ease of administration, and in particular one that gelled inthe nose upon contact with the nasal tissues, which could be used toadminister, and to modify absorption characteristics, of drugs(therapeutic agents) intended to act locally or systemically. It wouldalso be desirable to provide a system which is well accepted bypatients, does not enhance the absorption of drug intended for a localeffect into the systemic circulation (as this could lead to sideeffects), and comprises materials that are approved by regulatoryauthorities.

[0013] Those skilled in the art will appreciate that there are similarproblems to be solved in respect of drug delivery for the improvedtreatment of conditions that affect the vaginal cavity, the rectum, theeye, and the back of the throat, as well as for the improved delivery ofvaccines to the local lymphoid tissue, or for the improved delivery ofDNA for the transfection of epithelial cells.

[0014] For example, drugs intended for the treatment of vaginalinfections, or drug free formulations intended to act as vaginalmoisturizing agents (especially useful in post-menopausal conditions),should spread well in the vaginal cavity and be retained for longperiods of time. However, it has been reported that so-calledbioadhesive formulations that are intended to be retained in the vaginalcavity for days can be expelled rapidly, with more that 80% of the doseleaving the vagina in less than 2 hours (Brown, et al., 14, 1073(1997)). Thus, it would be advantageous to provide a single componentliquid composition that could be inserted into the vagina as a simpleliquid and that gelled under the local environmental conditions to givegood retention.

[0015] For rectal enemas, it would be most beneficial if the liquidenema formed a gel once applied, ensuring close contact with the localenvironment and preventing early discharge.

[0016] Similar problems may be identified in respect of administrationto the eye, by virtue of the fact that liquid formulations are rapidlycleared from the eye through drainage down the naso-lacrymal duct. Asingle component liquid composition that gelled upon application to theeye would be advantageous for the treatment of conditions such as eyeinfections and inflammation.

[0017] Pectins are materials which are found in the primary cell wall ofall green land plants. They are heterogeneous materials, with apolysaccharide backbone that is uniform as α-1,4-linked polygalacturonicacid. Various neutral sugars have been identified in pectins such asxylose, galactose, rhamnose, and arabinose.

[0018] A critical property of pectins which is known to affect theirgelation properties, is the extent to which the galacturonic acid unitsare esterified. The degree of esterification (DE) of pectins foundnaturally can vary considerably (from 60 to 90%). The term DE is wellunderstood by those skilled in the art and may be represented as thepercentage of the total number of carboxyl groups which are esterified,or as the methoxyl content of the pectin. The respective theoreticalmaximum for each is 100% and 16% respectively. DE as used herein refersto the total number of carboxyl groups which are esterified. Low DEpectins (i.e., those having less than 50% esterification) are usuallyprepared by the de-esterification of extracted pectins, normally on abench scale, by way of an enzymatic process, or, on an industrial scale,by the treatment with acid or ammonia in an alcoholic heterogeneousmedium. For pectins with a low degree of methoxylation (DM; less than45%) the gelation properties are known to depend on the DM and themolecular weight of the pectin. The chemistry of low methoxyl pectingelation is described by Axelos and Thibault in “The Chemistry andTechnology of Pectin”, Academic Press, New York, pp. 109-118, (1991).

[0019] Various prior art documents discuss the potential use of pectinas a bioadhesive and gelling material. Studies by Smart et al, J. Pharm.Pharmacol. 36, 295 (1984) in relation to the adhesiveness of variousmaterials to mucus have shown that pectin is poorly adhesive in in vitrotests. A tablet capable of adhering to the mucus membrane containingpectin has been described in EP 306 454. Oechslein et al (Int. J.Pharm., 139, (1994), 25-32), have described the potential of variouspowder formulations to enhance the nasal absorption of the somatostatinanalogue peptide octreotide. Pectin (type FPA) powder was used, and gaverise to an increase in the absolute bioavailability of the drug ascompared to the drug administered in a saline solution. In none of thesedocuments was the use of a solution formulation containing a pectin witha low DE, or a pectin that gels in contact with nasal secretions,described.

[0020] Pectin has also been studied as a mucoadhesive ophthalmicmaterial by Chetoni et al (Bull. Chem. Farm., 135, 147 (1996)). Saltcomplexes of drugs with pectin for administration to the oral mucosa aspatches have been described by Burgalassi et al, World Meet. Pharm.Biopharm. Pharm. Technol., (1995), p. 839, APGI, Paris. Popovici andSzasz (in “Buccal and Nasal Administration as Alternatives to ParenteralAdministration”, Minutes of a European Symposium (1992), Duchene, D.,Ed., Sante, Paris, France. p. 292-6) have described mucoadhesivehydrogels containing cellulose and pectin and a bivalent cation in theform of magnesium. The use of a low DE pectin as a solution that wouldgel in contact with mucosal surfaces was not described in any of thesedocuments.

[0021] U.S. Pat. No. 4,826,683 describes a nasal decongestant containingvegetable oil, aloe vera, zinc, vitamin C, vitamin A, vitamin E, vitaminB6, biotin, and fruit pectin. The content of fruit pectin was to amaximum of 2 g per liter. The solubilized fruit pectin supplied byGeneral Foods under the trade name “Certo” was preferred. JP 62236862describes an artificial mucus composed of a mixture of a spinnable watersoluble polymer and a polysaccharide, protein or vinyl polymer. Pectinis listed as a suitable polysaccharide, though the type of pectin is notspecified.

[0022] U.S. Pat. No. 5,147,648 (EP 289 512) describes a pharmaceuticalformulation made from at least two components which, when addedseparately, can form a gel for treating a mucosa. The two components areapplied separately to the same area of a mucous membrane. The componentsmay be added simultaneously or sequentially. One of the gel formingsolution components includes a calcium salt (e.g., calcium gluconate)and the other may include a pectin. There is no suggestion in this priorart document that a solution comprising pectin may be administered as asingle component, in the absence of a separately applied solution ofcalcium ions, which will gel once in contact with the mucosa.

[0023] U.S. Pat. No. 5,318,780 describes aqueous pharmaceutical vehiclescontaining two components, a film forming polymer (e.g., pectin) and anionic polysaccharide, which are then gelled in situ by contacting themixture with a counter-ion. Polygalacturonic acids such as pectin arementioned in an extensive listing of representative useful polymers forapplication in the eye as corneal mastis protective corneal shields. Noexamples of the use of a pectin solution alone, nor of pectins with alow DE, or pectins that would gel in contact with the mucosa, aredisclosed.

[0024] The preparation of pectin beads by ionotropic gelation has beendescribed by Aydin and Akburfa (1996) Int. J. Pharm., 137, 133-136.

[0025] In summary, although it is known in the art that all pectins willform gels in the presence of calcium ions, for the pectins employedpreviously in pharmaceutical systems to be applied to mucosal surfaces,it has been hitherto understood that high levels of calcium are needed,which levels are well above physiological concentrations. This hasnecessitated the utilization of pectin systems which are applied eitherin the form of preformed gels, or before or after the addition ofexogenous calcium in order to produce a gel in situ. That liquids(especially solutions) comprising low DE pectins may be applied as such,and may gel upon, or just after, application to mucosa is neitherdescribed nor suggested in any of the aforementioned prior artdocuments. Further, the importance of the DE of pectin upon suchgelation properties is not mentioned in any of these prior artdocuments.

BRIEF SUMMARY OF THE INVENTION

[0026] The invention provides a single component liquid pharmaceuticalcomposition for administration to a mucosal surface that includes (i) atherapeutic agent, (ii) a pectin with a low degree of esterification,(iii) and a aqueous carrier. The aqueous carrier gels or can be adaptedto gel at the site of application.

[0027] The invention also provides a kit of parts that includes a liquidpharmaceutical composition for administration to a mucosal surface. Thecomposition of the kit of parts includes a therapeutic agent, a pectinwith a low degree of esterification, and an aqueous carrier. Thecomposition gels or is adapted to gel at the site of application.Additionally, the kit does not include a solution of divalent metal ionsto be added extraneously to the surface. The kit of parts of theinvention may be packaged and presented with instructions to administerthe composition to the mucosal surface in the absence of an extraneoussource of divalent metal ions.

[0028] The invention is also directed to a pharmaceutical gelcomposition obtainable by applying a liquid composition, comprising atherapeutic agent, a pectin with a low degree of esterification, and anaqueous carrier for application to a mucosal surface of a mammalianpatient in the absence of extraneous application of a solution ofdivalent metal ions to the surface.

[0029] The invention also describes a method of treatment of a patient.The method comprises the administration of a liquid pharmaceuticalcomposition. The composition includes a therapeutic agent, a pectin witha low degree of esterification, and an aqueous carrier. The compositiongels or is adapted to gel at the site of application to a mucosalsurface of the patient in the absence of extraneous application of asolution of divalent metal ions to the surface.

[0030] Further described herein is a method of treatment of prophylaxisof a disease that comprises administration of a liquid pharmaceuticalcomposition. The composition includes a therapeutic agent that iseffective against the disease, a pectin with a low degree ofesterification, and an aqueous carrier. The composition gels or isadapted to gel at the site of the application. The composition isapplied to a mucosal surface of a patient in need of such treatment inthe absence of extraneous application of a solution of divalent metalions to the surface.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The foregoing summary, as well as the following detaileddescription of preferred embodiments of the invention, will be betterunderstood when read in conjunction with the appended drawings. For thepurpose of illustrating the invention, there is shown in the drawingsembodiments which are presently preferred. It should be understood,however, that the invention is illustrated, but in no way limited, bythe following examples with reference to the figures in which:

[0032]FIG. 1 shows the effect of systemic uptake of salmon calcitoninwhen administered intranasally to sheep in formulations comprising lowDE pectin.

[0033]FIG. 2 shows the cumulative release/diffusion of fexofenadine HClfrom HP-β-CD and HP-β-CD/pectin 100 solutions to simulated nasalelectrolyte solution.

DETAILED DESCRIPTION OF THE INVENTION

[0034] We have now found, surprisingly, that certain pectin materials,namely those with a low DE, may be administered in the form of singlecomponent, simple liquid formulations (i.e., in an aqueous carrier)which will gel, or can be readily adapted to gel, upon application tomucosa in the nasal, rectal, and vaginal cavities, in the eye, or at theback of the throat. We have also found, surprisingly, that gelation mayoccur at physiologically acceptable pH values in the presence of verymuch reduced calcium concentrations, i,e., those which can be foundphysiologically in the nasal secretions, as well as in the vaginallumen, the rectal cavity, and the tear fluid of the eye.

[0035] According to a first aspect of the invention there is provided asingle component liquid pharmaceutical composition for administration toa mucosal surface comprising a therapeutic agent, a pectin with a low DEand an aqueous carrier, that gels or can be adapted to gel at the siteof application.

[0036] We have found, in particular, that such compositions gel, or canbe adapted to gel, at the site of, and upon, or just after, applicationto a mucosal surface in the absence of an extraneously (i.e., separatelyand/or independently) applied (simultaneously or sequentially) solutionof calcium (or other divalent metal) ions. There is thus provided asingle component liquid pharmaceutical composition for applicationdirectly to a mucosal surface comprising a therapeutic agent, a pectinwith a low DE and an aqueous carrier, which composition is adapted togel at the site of application in the absence of an extraneous source(e.g., solution) of divalent metal ions applied to the same site.

[0037] According to a further aspect of the invention, there is provideda kit of parts comprising a liquid pharmaceutical composition foradministration to a mucosal surface, comprising a therapeutic agent, apectin with a low DE and an aqueous carrier, provided that the kit doesnot comprise a solution of divalent metal ions to be added extraneouslyto the surface.

[0038] In particular, there is provided a kit of parts comprising aliquid pharmaceutical composition for administration to a mucosalsurface, which composition comprises a therapeutic agent, a pectin witha low DE and an aqueous carrier, and which kit of parts is packaged andpresented with instructions to administer the composition to the surfacein the absence of an extraneous source of divalent metal ions.

[0039] The liquid pharmaceutical compositions for administration tomucosal surfaces comprising therapeutic agent, low DE pectin and aqueouscarrier, which are, or are to be, administered as a single component,and which gel, or are adapted to gel, in the absence of an extraneoussource of divalent metal ions are referred to hereinafter as “thecompositions of the invention”.

[0040] By “liquid” composition, we mean a composition which is in theform of a mobile fluid upon application to the mucosa. The compositionsof the invention are in the form of an aqueous formulation comprising asolution, a suspension, or an emulsion, including pectin and therapeuticagent, in water. The compositions of the invention will gel, or may beadapted to gel, upon, or shortly (e.g., up to 5 minutes) after,application, to a form a solid or semi-solid gel material, which gel issuitable to provide a retaining effect at the site of administration.

[0041] By “degree of esterification (DE)”, it is meant the percentage ofgalacturonic acid units which are esterified, for example as describedin the article by Walter in “The Chemistry and Technology of Pectin”,Academic Press, New York (1991), p. 192. By “low DE”, it is meant apectin in which less than 50%, and more preferably less than 35%, of thegalacturonic acid units are esterified.

[0042] The term “extraneous source” of divalent metal ions includes aseparate and/or independent (i.e. exogenous) source of such ions. Ionswhich are present in a gel resulting from administration of acomposition of the invention to a mucosa are not derived from either thecomposition, or from the bodily secretions of the patient to which thecomposition is to be applied (e.g., endogenous ions derived from nasalsecretions, tear fluid, etc.). Divalent metal ions which may bementioned include calcium ions.

[0043] According to a further aspect of the invention, there is provideda pharmaceutical gel composition obtainable by applying a liquidcomposition, comprising a therapeutic agent, a pectin with a low DE andan aqueous carrier, to a mucosal surface of a mammalian patient in theabsence of extraneous application of a solution of divalent metal ionsto the surface.

[0044] The gels so formed upon contact with mucosal surfaces willcontain only endogenous divalent metal ions (i.e., those deriveddirectly from bodily secretions) and will not include exogenous divalentmetal ions (i.e., those derived from an extraneous source). According toa further aspect of the invention there is provided a pharmaceutical gelcomposition, which gel comprises a therapeutic agent and a pectin with alow DE, which gel is obtainable by applying a liquid composition,comprising the therapeutic agent and pectin in an aqueous carrier, to amucosal surface, and which gel is substantially free of divalent metalions derived from an extraneous source applied to the mucosal surfacebefore, or at the same time as, or after, the liquid composition isapplied.

[0045] Because the compositions of the invention are not added inconjunction with an extraneous source of such ions, by “substantiallyfree” of divalent metal ions, it is meant greater than 97%, preferablygreater than 99%, more preferably greater than 99.9%, and especiallygreater than 99.99% free.

[0046] Pectins with a low DE can be obtained from known sources, or canbe obtained via de-esterification of high DE pectins (which may beobtained from, for example, Sigma Fine Chemicals), in accordance withknown techniques, such as those described in the article by Rollin in“Industrial Gums”, Academic Press, New York (1993) p. 257, or asdescribed hereinbefore. Low DE pectin may, for example, be obtained fromCopenhagen Pectin A/S as the commercial material known as Slendid Type100 and Slendid Type 110. These pectins have been extracted from citruspeel and standardized by the addition of sucrose. The standardizationprocess is as described by Rollin in the above-mentioned article. The DEis less than 50% for both pectins and of the order of 10% for type 100and 35% for type 110. Further materials which may be employed includeGENU pectin types LM 1912 CS and Pomosin pectin types LM 12 CG and LM 18CG.

[0047] The compositions of the invention may be prepared by dissolvingor dispersing the pectin of low DE and therapeutic agent in an aqueoussystem, to form a solution, a suspension or an emulsion in accordancewith known techniques. For example, the therapeutic agent may bedissolved in a prior prepared aqueous solution of the pectin, or may beadded as, or to form, a suspension in an aqueous system, where the drugparticles are less than 100 microns in size, preferably between 1 and 20microns. Alternatively, drug may be dissolved or suspended in a suitableoily vehicle such as a vegetable oil, and then dispersed into theaqueous pectin solution to form an emulsion. It will be appreciated bythose skilled in the art that the type of aqueous formulation sodeveloped will depend upon to mucosa to be treated, as well as the dose,and the physical characteristics and properties, of the drug (e.g., itssolubility, basicity etc.).

[0048] The concentration of low DE pectin in compositions of theinvention depends upon the nature of the pectin, the presence of othercomponents, and other factors which influence gelation properties of thecomposition (see below), but may be from 1 g/L to 100 g/L, and ispreferably from 1 g/L to 50 g/L, more preferably from 2 g/L to 10 g/Land especially from 5 g/L to 10 g/L.

[0049] Compositions of the invention may be used with a view to theprevention of a major problem in the delivery of drugs to the nose forlocal treatment, namely the rapid mucociliary clearance mechanism. Thisnatural process, which removes deposited material from the front of thenose to the throat, can clear material from the nose with a half-time ofabout 10 to 20 minutes. Such clearance rates can be measured readily inman using the saccharin clearance test or by gamma scintigraphy (Aspdenet al, J. Pharm. Sci., 86, 509 (1997); Illum et al, Int. J. Pharm., 39(1987) 189-199).

[0050] Compositions of the invention may be employed to retain atherapeutic agent which is intended to act locally at a mucosal surfacefor a relatively long period when compared to mucosal delivery systemsknown in the art. If the therapeutic agent is easily absorbed,absorption may be retarded, thus keeping more of the drug at the site ofapplication, where it is needed.

[0051] Therapeutic agents which may be employed in the compositions ofthe invention include, for nasal administration, drugs that are employedlocally to treat conditions such as rhinitis, viral infections, as wellas those which act as decongestants. The compositions of the inventionmay also be used as a way of improving the delivery of vaccines to thenose associated lymphoid tissue and for the better presentation of DNAfor the transfection of nasal epithelial cells.

[0052] The following list of therapeutic agents are suitable for use inthe compositions of the invention, for local treatment of a mucosalsurface, is provided by way of illustration and is not meant to beexclusive: antiviral agents such as ICAM-1, pirovadir, acyclovir,bromovinyldeoxyuridine, α, β and γ-interferon, zidovudine; decongestantssuch as oxymetazaline; anti-allergic agents, such as sodium cromoglycateand budesonide; steroids, such as fluticazone; vaccines, such as DNA,influenza, pertussis, measles and diphtheria vaccines; antibacterialagents; antifungal agents, such as amphotericin, nystatin; contraceptiveand/or spermicidal agents; antibodies especially for the treatment ofRSV infection in children; prophylactic agents against HIV;antihistamines, such as diphenhydramine hydrochloride; and genes.

[0053] Combinations of the above-mentioned therapeutic agents may alsobe employed.

[0054] Compositions of the invention may also be employed to control theplasma level versus time profile for readily absorbable drugs which areintended to act systemically (i.e., to give a flatter profile), eitherby altering the rate of transport into the general circulation, or byretarding absorption of readily absorbable drugs. This can, for example,be of importance when side effects from high peak plasma levels are tobe avoided.

[0055] The compositions of the invention may thus be used for themodification of the systemic absorption of mucosally administered drugs,including, but not limited to, apomorphine, nicotine, hyoscinehydrobromide, lignocaine, fentanyl, naratriptan, pheromones andpropranolol.

[0056] Combinations of the above-mentioned therapeutic agents may alsobe employed.

[0057] The term “therapeutic agents” is intended herein to includeagents which are suitable for use in the treatment, and in theprevention, of disease.

[0058] The compositions of the invention may be used to treat/preventdiseases/conditions in mammalian patients depending upon the therapeuticagent(s) which is/are employed. For the above, non-exhaustive lists oflocally acting and systemic drugs, diseases/conditions which may bementioned include those against which the therapeutic agent(s) inquestion are known to be effective, and include those specificallylisted for the drugs in question in Martindale, “The ExtraPharmacopoeia”, 31st Edition, Royal Pharmaceutical Society (1996).

[0059] Preferred drugs include nicotine and apomorphine.

[0060] The amount of therapeutic agent which may be employed in thecompositions of the invention will depend upon the agent which is used,and the disease to be treated, but may be in the range 0.01 to 40% w/w.However, it will be clear to the skilled person that suitable doses oftherapeutic agents can be readily determined non-inventively. Forexample, estimates of dosage can be made from known injectable productsassuming that from 0.1 to 90% of the dose is absorbed. Suitable singleunit doses are in the range 10 μg to 500 mg depending upon thetherapeutic agent(s) which is/are employed and the route ofadministration. Suitable daily doses are in the range 10 μg to 1 g/daydepending upon the therapeutic agent(s) which is/are employed and theroute of administration.

[0061] Most compositions comprising drug and a low DE pectin will gelupon application at the site of application, i.e., upon, or shortly(e.g., up to 5 minutes) after, contact with the relevant mucosalsurface. However, in some formulations, the nature of the drug and/orthe pectin which is/are employed may require that the composition isadapted such that it gels upon, or shortly (e.g., up to 1 minute) after,contact. This may be achieved readily via techniques which are wellknown to those skilled in the art:

[0062] For example, the concentration of pectin may be selected suchthat the aqueous formulation will gel once in contact with the mucosalsurface.

[0063] Furthermore, the addition of monovalent ions to aid the gellingprocess may be required (for example, simple monovalent electrolytes,e.g., NaCl, may be added to adapt the liquid formulation to gel, as wellas to provide isotonicity).

[0064] The quantity and nature of the drug in the aqueous formulationmay also have an influence on the gelation properties. For example, theaddition of a high level of a certain drugs, including those which areweak bases (such as nicotine), which are known to form reversiblecomplexes with anionic materials such as pectin, may require a change inthe ratio between drug and pectin, so that preferably 30%, morepreferably 50%, and most preferably 60%, of the negative charges on thepectin molecule are uncomplexed.

[0065] Alternatively, sugars in the form of, for example, sucrose can beadded to the formulation to aid gelation. Non-ionic polysaccharides(such as hydroxypropyl methyl cellulose) may also be used.

[0066] The pH of the composition has also been found to affect gelationproperties. The pH of the compositions of the invention may be from 2 to9, more preferably from 3 to 8 and most preferably from 4 to 7, takinginto account the gelation properties of the composition and theproperties of the therapeutic agent. For example, in general, we havefound that the lower the DE of the pectin, the lower the pH at which thecomposition will gel. pH may be adjusted in accordance with techniqueswhich will be well known to those skilled in the art, such as theaddition of pharmaceutically acceptable buffering agents, especiallythose of low ionic strength. Axelos and Thibault in “The Chemistry andTechnology of Pectin”, Academic Press, New York, pp. 109-118, (1991)describe how the gelation properties of low DE pectin solutions aresomewhat sensitive to pH and ionic strength.

[0067] The above-mentioned techniques, which may be used to adapt thecompositions of the invention to gel, may be investigated and determinedin the normal course of routine experimentation by those skilled in theart. Combinations of these techniques may also be employed in order toaffect gelation properties.

[0068] The compositions may also contain other additives in the form ofpharmaceutical excipients, such as preservatives (e.g., lowconcentrations of materials such as sodium metabisulphate), stabilizers,flavoring agents, absorption enhancers such as bile salts,phospholipids, as well as agents which are known to interact with thedrug, for example to form inclusion or salt-bridge complexes, andpromote a controlled release in the nasal cavity from the formed gel,such as cyclodextrins and ion exchange resins.

[0069] Additional pharmaceutically acceptable excipients which may beadded to the compositions of the invention include agents such asglycerol.

[0070] According to a further aspect of the invention there is provideda process for the preparation of a composition of the invention whichcomprises mixing together the therapeutic agent and the pectin in theaqueous carrier.

[0071] The compositions of the invention may be administered in suitabledosage forms, in accordance with techniques, and via delivery devices,all of which are known to those skilled in the art. For example, fornasal delivery, the compositions of the invention are preferablyadministered by way of a spray device, for example the Pfeiffer metereddose pump or the Valois metered dose pump, or via a liquid free flowsystem (such as nasal drops). For vaginal and rectal administration(infusion) a syringe-type applicator may be used, or plastics ampoulesfitted with a suitable nozzle, where the contents of the ampoule can bedelivered to the vaginal or rectal surface via the application of aslight pressure. Suitable systems for delivery of the compositions ofthe invention to the back of the throat include spray devices which arewell known to those skilled in the art. Suitable systems for delivery ofthe compositions of the invention to eye include liquid free flow systemwhich are well known to those skilled in the art (such as eye drops).

[0072] The compositions of the invention have the advantage that theymay be readily administered to mucosal surfaces in the form of singlecomponent, simple liquid formulations, in the absence of an additionalcomponent comprising an extraneous source of divalent metal ions, usingdevices which are well known to those skilled in the art. Thecompositions of the invention also have the advantage that they gelupon, or shortly after, contact with mucosa, at physiologicallyacceptable pHs, in the presence of endogenous calcium (only) foundphysiologically in the nasal secretions, as well as in the vaginallumen, the rectal cavity and the tear fluid of the eye.

[0073] Compositions of the invention also have the advantage that theymay be used to retain a locally-acting drug at a mucosal surface, or tocontrol drug absorption into the systemic circulation.

[0074] Compositions of the invention may also have the advantage thatthey may be well accepted by patients, and may comprise materials thatare approved by regulatory authorities.

[0075] According to a further aspect of the invention there is provideda method of treatment of a patient which comprises the administration ofa liquid pharmaceutical composition, comprising a therapeutic agent, apectin with a low DE and an aqueous carrier, which composition gels oris adapted to gel at the site of application, to a mucosal surface ofthe patient in the absence of extraneous application of a solution ofdivalent metal ions to the surface.

[0076] There is provided further a method of treatment or prophylaxis ofa disease which comprises administration of a composition of theinvention including a therapeutic agent which is effective against thedisease to a mucosal surface of a patient in need of such treatment inthe absence of extraneous application of a solution of divalent metalions to the surface.

EXAMPLE 1

[0077] To Demonstrate that Pectins with Low DEs Gel Under SimulatedConditions of the Nasal Cavity while Pectins with Higher DEs Do Not

[0078] Materials:

[0079] Pectin, esterified, potassium salt (DE: 31%; lot 22H0548; Sigma)

[0080] Pectin, esterified, potassium salt (DE: 67%; lot 74H1093; Sigma)

[0081] Pectin, esterified (DE: 93%; lot 125H0123; Sigma).

[0082] Pectin, Slendid type 100 (lot 620970; Hercules; Denmark).

[0083] Pectin, Slendid type 110 (lot 626790; Hercules, Denmark).

[0084] Pectin, GENU type LM 12 CG (lot G 63481; Pomosin GmbH; Hercules;,Germany).

[0085] Pectin, GENU type LM 18 CG (lot G 63484; Pomosin GmbH; Hercules;Germany).

[0086] Sodium chloride (BDH).

[0087] Potassium chloride (BDH).

[0088] Calcium chloride dehydrate (Sigma).

[0089] A simulated nasal electrolyte (SNES) solution was prepared,composed of the following ingredients: Sodium chloride 8.77 g/LPotassium chloride 2.98 g/L Calcium chloride dehydrate 0.59 g/L

[0090] The SNES was prepared in double strength:

[0091] 3.508 g of sodium chloride, 1.192 g of potassium chloride and0.236 g of calcium chloride dehydrate were weighed into three weighingboats respectively, and

[0092] dissolved and transferred into a 200 mL volumetric flask.

[0093] The solution was stirred on a magnetic stirrer until the drug haddissolved.

[0094] Water was added to volume.

[0095] Preparation of 20 g/L pectin solutions

[0096] 1 g of each type of pectin was weighed into a 100 mL bottle.

[0097] 50 mL of ultrapure water was added to each bottle.

[0098] The content was stirred on a magnetic stirrer until pectin haddissolved, and

[0099] the pH of the solution was measured and adjusted to pH 4 or pH6.5 with 0.1M sodium hydroxide solution.

[0100] Preparation of various formulations containing SNES and pectinwith different concentrations (2 to 10 g/L)

[0101] Appropriate volumes of 20 g/L pectin solution, to obtain thefinal concentrations of 2, 3, 4, 5, 6, 7, 8, 9 and 10 g/L, were measuredin a series of 10 mL screw capped glass tubes.

[0102] Appropriate volumes of water were added to obtain a total volumeof 2.5 mL firstly, then 2.5 mL of the two fold concentration SNES wasadded.

[0103] The tubes were cooled in an ice water bath for 15 minutes.

[0104] The test tubes were tilted to check the phase state and flowproperty.

[0105] The tubes were vigorously shaken to check the phase state andflow property again.

[0106] Results

[0107] The results are shown in Table 1:

[0108] 1. Pectin type 100 and 110 gelled with simulated nasalelectrolyte solution when the final concentration of pectin was >2 g/Land formed a strong gel when the final concentration was >4 g/L at pHvalues of 4 and 6.5. The gel was transparent and homogeneous. Thestrength of gel increased with the increasing pectin concentration insystem.

[0109] 2. Pectin type LM 12 CG and LM 18 CG gelled at final pectinconcentrations of 4 g/L and 6 g/L (pH 4) and 4 g/L (pH 6.5)respectively. These two pectin types only formed solid gels at pH 6.5and at concentrations higher than 6 g/L and 8 g/L respectively.

[0110] 3. Pectin with a DE of 31% (Sigma) gelled at a concentrationof >2 g/L and formed a solid gel at concentrations >4 g/L. Pectin 67%and 93% did not form solid gels at concentrations up to 10 g/L atneither pH 4 nor at pH 6.5.

EXAMPLE 2

[0111] Nasal Drug Formulation Prepared from Pectins with Low Des

[0112] Formulations were prepared containing drugs in the form ofnicotine (a weak base) and cromolyn sodium (sodium cromoglycate; a weakacid). Pectin formulations were prepared at a pectin concentration of 10mg/mL using Slendid 100 and Slendid 110. The formulations were mixedwith the simulated nasal electrolyte solution (the method of preparationof which was as in Example 1). The formulations were filled into a nasaldelivery device (Pfeiffer metered dose pump) and the spray propertiesevaluated by visual examination.

[0113] The gelation of the formulation in the nasal electrolyte solutionwas evaluated as solution, gel or solid by visual observation and theflow properties before and after shaking. The results, which are set outin Table 2, show that when the formulation contained a weak acid(cromolyn sodium), gelation occurred in the nasal electrolyte solution.When the formulation contained a high level of a weak base (nicotine)then gelation did not occur.

[0114] It is believed that the reason for this difference is that theionized nicotine may interact with the charged carboxyl groups on thepectin molecules and thereby influence the gelation characteristics ofthe low esterified pectin. Thus, with weakly basic drugs, a personskilled in the art is able to adjust the pectin concentration to takethis interaction into account (see above).

EXAMPLE3

[0115] To Demonstrate that Nasal Formulations containing Low DE Pectindo not Enhance the Systemic Uptake of a Poorly Absorbed Drug

[0116] For the local delivery of drugs it is important to retain thedrug at its site of action, namely the nasal, rectal and vaginalcavities. In such cases, the formulation should not enhance theabsorption of the drug. It is known that some bioadhesive gellingformulations may increase systemic uptake. Therefore, experiments havebeen conducted in an animal model to demonstrate that pectins with lowDE do not enhance the nasal uptake (systemically) of a model polar drug,salmon calcitonin (S-CT).

[0117] Sheep

[0118] Eight female, cross-bred sheep of known weight were used in thisstudy. The average weight of the sheep was in the region of 60 kg. Thesheep were weighed and labeled 1 to 8. An in-dwelling Secalon cannulafitted with a flowswitch was placed approximately 15 cm into one of theexternal jugular veins of each animal on the first day of the study.Whenever necessary, the cannula was kept patent by flushing it withheparinised (25 IU/mL) 0.9% saline solution. This cannula remainedin-dwelling in the jugular vein of each animal for the duration of thestudy and was removed upon completion of the study.

[0119] Preparation of salmon calcitonin (S-CT) formulations

[0120] Two S-CT formulations were prepared. Each formulation contained2000 IU/mL S-CT, which was sufficient material to administer a dose of20 IU/kg in a volume of 0.01 mL/kg. The sheep were randomly divided intotwo groups of four animals and each group was dosed with a differentS-CT formulation.

[0121] Summary of the dose groups S-CT Chitosan G210 Pectin Slendid 100Formulation (IU/kg) (mg/kg) (mg/kg) I 20 — — II 20 — 0.1

[0122] Prior to dose administration the sheep were sedated with anintravenous dose of Ketamine Vetalar® (100 mg/mL injection) at 2.25mg/kg. Intranasal doses were administered at 0.01 mL/kg. The dose wasdivided equally between each nostril. For dose administration, ablueline umbilical cannula was inserted into the nostril of the sheep toa depth of 10 cm, before the delivery of the appropriate volume ofsolution from a 1 mL syringe.

[0123] Blood sampling

[0124] Blood samples of 4 mL were collected from the cannulated jugularvein of the sheep at 15 and 5 minutes prior to S-CT administration andat 5, 15, 30, 45, 60, 90, 120, 150, 180, 240, 300, 360, 420 and 480minutes post-administration. They were then mixed gently in 4 mLheparinised tubes and kept on crushed ice before plasma separation.Plasma was separated by centrifugation for 10 minutes at 4° C.approximately 3000 rpm. Each plasma sample was divided into two equalaliquots of approximately 1 mL and stored at −20° C. One set of plasmasamples was used for calcium analysis.

[0125] Calcium analysis

[0126] Plasma calcium analysis was performed by the Clinical ChemistryDepartment, Queens Medical Centre, University of Nottingham. The resultsshowed that for the formulation I and II the plasma calcium levels werevery similar and that the presence of pectin in the formulation did notlead to an increase in the systemic bioavailability of the model drug.

EXAMPLE 4

[0127] Simulated Nasal Electrolyte Solution-Pectin Gelling System forControlled Release of Fexofenadine Hydrochloride

[0128] Preparation of Formulations

[0129] Formulation 1-10 mg/mL fexofenadine HCl100 mg/mL HP-β-CD: 2 g ofHP-β-CD was dissolved in 18-19 mL of water in a 20 mL volumetric flask.200 mg of fexofenadine was added to the solution and stirred until thedrug has dissolved. The pH of the solution was adjusted to 4.0, then thesolution was made up to volume with water.

[0130] Formulation 2-10 mg/mL fexofenadine HCl/100 mg/mL HP-β-CD/10mg/mL pectin 100:

[0131] 50 mg of pectin 100 (SLENDID type 100, Hercules, Denmark) wasdissolved in 5 mL of Formulation 1 in a 5 mL volumetric flask.

[0132] Release/Diffusion Testing

[0133] A Franz diffusion cell apparatus was set up in a closed looparrangement and parameters were listed as follows:

[0134] Medium: Simulated nasal electrolyte solution

[0135] Temperature: 37° C.

[0136] Membrane: Cellulose nitrate, 0.45 Tm pore size

[0137] Volume of the closed loop arrangement: 8.8 mL

[0138] Stirring speed of a magnetic stirrer: 4

[0139] Peristaltic pump flow rate: 1 (The Cole-Parmer Masterflexperistaltic pump, Model 7518-60, fitted with Masterflex L/Sth 14silicone tubing)

[0140] Sample volume: 0.4 mL (contained 4 mg of fexofenadine HCl, themaximum concentration of the drug in medium will be around 450 Tg/mL)

[0141] Wavelength: 260 nm

[0142] Results

[0143] The results are shown in FIG. 2. (Every point on the graphsrepresents a mean value of two points.)

[0144] The maximum UV absorbance of Formulation 1 (control) reachedduring the diffusion experiment was used as 100% release to calculatethe percentage of release at each selected time point.

[0145] The results show a clear difference in release characteristics ofthe two formulations.

[0146] It will be appreciated by those skilled in the art that changescould be made to the embodiments described above without departing fromthe broad inventive concept thereof. It is understood, therefore, thatthis invention is not limited to the particular embodiments disclosed,but it is intended to cover modifications within the spirit and scope ofthe present invention as defined by the appended claims.

We claim:
 1. A single component liquid pharmaceutical composition foradministration to a mucosal surface comprising a therapeutic agent, apectin with a low degree of esterification and an aqueous carrier, thatgels or can be adapted to gel at the site of application.
 2. Acomposition as claimed in claim 1, wherein the mucosal surface is thenasal cavity.
 3. A composition as claimed in claim 1, wherein themucosal surface is the vagina.
 4. A composition as claimed in claim 1,wherein the mucosal surface is the rectum.
 5. A composition as claimedin claim 1, wherein the mucosal surface is the back of the throat.
 6. Acomposition as claimed in claim 1, where the mucosal surfaces is theeye.
 7. A composition as claimed in claim 1, which is administered as aspray or a liquid free flowing system.
 8. A composition as claimed inclaim 1, wherein the degree of esterification is less than 50%.
 9. Acomposition as claimed in claim 1, wherein the pectin concentration inthe composition is from 1 to 100 g/L.
 10. A composition as claimed inclaim 1, wherein the pH of the composition is between 2 and
 9. 11. Acomposition as claimed in claim 1, for use in the delivery of anantiviral agent to the nose or the vagina.
 12. A composition as claimedin claim 1, for use in the delivery of a vaccine to the nose, the rectumor the vagina.
 13. A composition as claimed in claims 1, for use in thedelivery of a decongestant agent.
 14. A composition as claimed in claims1, for use in the delivery of a contraceptive agent.
 15. A compositionas claimed in claim 1, for use as a vaginal lubricating agent.
 16. Acomposition as claimed in claim 1, for use in the delivery of ananti-allergic agent.
 17. A pharmaceutical formulation in a form suitablefor administration to a mucosal surface, which formulation comprises acomposition according to claim 1 in a pharmaceutically acceptable dosageform.
 18. A formulation as claimed in claim 17, which is in the form ofa spray or a liquid free flowing system.
 19. The use of a compositionaccording to claim 1, as a means of delivery of therapeutic agents tothe nose, the vagina, the rectum, the back of the throat or the eye. 20.A kit of parts comprising a liquid pharmaceutical composition foradministration to a mucosal surface, comprising a therapeutic agent, apectin with a low degree of esterification and an aqueous carrier, whichcomposition gels or is adapted to gel at the site of application,provided that the kit does not comprise a solution of divalent metalions to be added extraneously to the surface.
 21. A kit of partscomprising a liquid pharmaceutical composition for administration to amucosal surface, which composition comprises a therapeutic agent, apectin with a low degree of esterification and an aqueous carrier, whichcomposition gels or is adapted to gel at the site of application, andwhich kit of parts is packaged and presented with instructions toadminister the composition to the surface in the absence of anextraneous source of divalent metal ions.
 22. A kit of parts comprisinga composition according to claim 1, which kit of parts is packaged andpresented with instructions to administer the composition or formulationto a mucosal surface in the absence of an extraneous source of divalentmetal ions.
 23. A pharmaceutical gel composition obtainable by applyinga liquid composition, comprising a therapeutic agent, a pectin with alow degree of esterification and an aqueous carrier, to a mucosalsurface of a mammalian patient in the absence of extraneous applicationof a solution of divalent metal ions to the surface.
 24. Apharmaceutical gel composition comprising a therapeutic agent and apectin with a low degree of esterification, which gel is obtainable byapplying a liquid composition, comprising the therapeutic agent andpectin in an aqueous carrier, to a mucosal surface, and which gel issubstantially free of divalent metal ions derived from an extraneoussource applied to the mucosal surface before, or at the same time as,the liquid composition is applied.
 25. A pharmaceutical gel compositionobtainable by administering a composition according to claim 1, to amucosal surface of a mammalian patient in the absence of extraneousapplication of a solution of divalent metal ions to the surface.
 26. Amethod of treatment of a patient which comprises the administration of aliquid pharmaceutical composition, comprising a therapeutic agent, apectin with a low degree of esterification and an aqueous carrier, whichcomposition gels or is adapted to gel at the site of application, to amucosal surface of the patient in the absence of extraneous applicationof a solution of divalent metal ions to the surface.
 27. A method oftreatment or prophylaxis of a disease which comprises administration ofa liquid pharmaceutical composition, comprising a therapeutic agentwhich is effective against the disease, a pectin with a low degree ofesterification and an aqueous carrier, which composition gels or isadapted to gel at the site of application, to a mucosal surface of apatient in need of such treatment, in the absence of extraneousapplication of a solution of divalent metal ions to the surface.
 28. Amethod for delivering a therapeutic agent in a liquid formulation to thenose, eye, rectum, back of throat or vagina which comprises the deliveryof the agent in a composition according to claim
 1. 29. A method oftreatment of a mammalian patient which comprises administration of acomposition according to claim 1 to such a patient.
 30. A method for thedelivery of therapeutic agents to a mucosal surface in a mammal, whichcomprises administering a composition, as defined in claim 1 to thesurface.
 31. The use of a composition according to claim 1, as a meansof delivery of therapeutic agents to the nose, vagina, rectum, back ofthe throat, or eye.
 32. The use of a composition according to claim 1,in the manufacture of a medicament for the delivery of a therapeuticagent to the nose, vagina, rectum, back of the throat, or eye.
 33. Theuse of a composition according to claim 1, in the manufacture of amedicament for the treatment or prophylaxis of a disease which comprisesadministration of the composition, including a therapeutic agent whichis effective against the disease, to a mucosal surface of a patient inneed of such treatment or prophylaxis, in the absence of extraneousapplication of a solution of divalent metal ions to the surface.
 34. Theuse of a pectin with a low degree of esterification in the manufactureof a single component liquid composition for the delivery of therapeuticagents to mucosal surfaces.
 35. The use of a composition according toclaim 1, in the manufacture of a medicament for use in a method oftreatment according to any one of claims 26 to
 30. 36. A compositioncomprising a therapeutic agent, a pectin with a low degree ofesterification and an aqueous carrier, which composition is packaged andpresented for use in the treatment of a patient, which treatmentcomprises the administration of the composition to a mucosal surface ofthe patient in the absence of extraneous application of a solution ofdivalent metal ions to the surface.
 37. The use of a pectin with a lowdegree of esterification in the manufacture of an aqueous liquidpharmaceutical composition for the treatment of a patient comprising theadministration of the composition to a mucosal surface of the patient inthe absence of extraneous application of a solution of divalent metalions to the surface.
 38. A process for the preparation of a compositionaccording to claim 1, which comprises mixing together the therapeuticagent and the pectin in the aqueous carrier.
 39. A product obtainable bya process according to claim 38.